MolMod – an open access database of force fields for molecular simulations of fluids

The MolMod database is presented, which is openly accessible at http://molmod.boltzmann-zuse.de and contains intermolecular force fields for over 150 pure fluids at present. It was developed and is maintained by the Boltzmann-Zuse Society for Computational Molecular Engineering (BZS). The set of molecular models in the MolMod database provides a coherent framework for molecular simulations of fluids. The molecular models in the MolMod database consist of Lennard-Jones interaction sites, point charges, and point dipoles and quadrupoles, which can be equivalently represented by multiple point charges. The force fields can be exported as input files for the simulation programmes ms2 and ls1 mardyn, GROMACS, and LAMMPS. To characterise the semantics associated with the numerical database content, a force field nomenclature is introduced that can also be used in other contexts in materials modelling at the atomistic and mesoscopic levels. The models of the pure substances that are included in the database were generally optimised such as to yield good representations of experimental data of the vapour–liquid equilibrium with a focus on the vapour pressure and the saturated liquid density. In many cases, the models also yield good predictions of caloric, transport, and interfacial properties of the pure fluids. For all models, references to the original works in which they were developed are provided. The models can be used straightforwardly for predictions of properties of fluid mixtures using established combination rules. Input errors are a major source of errors in simulations. The MolMod database contributes to reducing such errors.     

The effect of leucotriene C4 and D4 on cutaneous blood flow in humans

Using a laser-Doppler-flowmeter the microvascular response to LTC₄ and LTD₄ was measured. Intradermal injection of 1 Ug LTC₄ and LTD₄ caused an increase in the microvascular cutaneous bloodflow. The increase in flow was equal to that caused by histamine in equimolar amounts. Blocking the triple-response did not change the response. The values measured after injection of histamine and leucotrienes were about 10–15 times the values found in undisturbed skin and represents probably a maximally dilated vascular bed. Injection of the leucotrienes caused a slight sensation of pain.     

Do PTK2 gene polymorphisms contribute to the interindividual variability in muscle strength and the response to resistance training? A preliminary report

The protein tyrosine kinase-2 (PTK2) gene encodes focal adhesion kinase, a structural protein involved in lateral transmission of muscle fiber force. We investigated whether single-nucleotide polymorphisms (SNPs) of the PTK2 gene were associated with various indexes of human skeletal muscle strength and the interindividual variability in the strength responses to resistance training. We determined unilateral knee extension single repetition maximum (1-RM), maximum isometric voluntary contraction (MVC) knee joint torque, and quadriceps femoris muscle specific force (maximum force per unit physiological cross-sectional area) before and after 9 wk of knee extension resistance training in 51 untrained young men. All participants were genotyped for the PTK2 intronic rs7843014 A/C and 3'-untranslated region (UTR) rs7460 A/T SNPs. There were no genotype associations with baseline measures or posttraining changes in 1-RM or MVC. Although the training-induced increase in specific force was similar for all PTK2 genotypes, baseline specific force was higher in PTK2 rs7843014 AA and rs7460 TT homozygotes than in the respective rs7843014 C- (P = 0.016) and rs7460 A-allele (P = 0.009) carriers. These associations between muscle specific force and PTK2 SNPs suggest that interindividual differences exist in the way force is transmitted from the muscle fibers to the tendon. Therefore, our results demonstrate for the first time the impact of genetic variation on the intrinsic strength of human skeletal muscle.     

Developmental exposure to noninherited maternal antigens induces CD4+ T regulatory cells: relevance to mechanism of heart allograft tolerance

We hypothesize that developmental exposure to noninherited maternal Ags (NIMA) results in alloantigen-specific natural and adaptive T regulatory (T(R)) cells. We compared offspring exposed to maternal H-2(d) (NIMA(d)) with nonexposed controls. In vitro assays did not reveal any differences in T cell responses pretransplant. Adoptive transfer assays revealed lower lymphoproliferation and greater cell surface TGF-beta expression on CD4(+) T cells of NIMA(d)-exposed vs control splenocytes. NIMA(d)-exposed splenocytes exhibited bystander suppression of tetanus-specific delayed-type hypersensitivity responses, which was reversed with Abs to TGF-beta and IL-10. Allospecific T effector cells were induced in all mice upon i.v. challenge with B6D2F1 splenocytes or a DBA/2 heart transplant, but were controlled in NIMA(d)-exposed mice by T(R) cells to varying degrees. Some (40%) NIMA(d)-exposed mice accepted a DBA/2 allograft while others (60%) rejected in delayed fashion. Rejector and acceptor NIMA(d)-exposed mice had reduced T effector responses and increased Foxp3(+) T(R) cells (CD4(+)CD25(+)Foxp3(+) T(R)) in spleen and lymph nodes compared with controls. The key features distinguishing NIMA(d)-exposed acceptors from all other mice were: 1) higher frequency of IL-10- and TGF-beta-producing cells primarily in the CD4(+)CD25(+) T cell subset within lymph nodes and allografts, 2) a suppressed delayed-type hypersensitivity response to B6D2F1 Ags, and 3) allografts enriched in LAP(+), Foxp3(+), and CD4(+) T cells, with few CD8(+) T cells. We conclude that the beneficial NIMA effect is due to induction of NIMA-specific T(R) cells during ontogeny. Their persistence in the adult, and the ability of the host to mobilize them to the graft, may determine whether NIMA-specific tolerance is achieved.     

Nitric oxide synthase inhibitor and IL-18 enhance the anti-tumor immune response of rats carrying an intrahepatic colon carcinoma

The role of nitric oxide (NO) produced by adherent spleen cells in the systemic immunosuppression developing in tumor-bearing hosts was investigated. After therapeutic immunization of rats carrying an intrahepatic colon carcinoma, H1D2, the spleen cell antitumor immune responsiveness was analyzed. Compared to parallel immunized tumor-free rats, tumor-bearing rats (TB rats) had a greatly reduced proliferative T-cell response to wild-type tumor stimulator cells. The TB rats had a depressed proliferative response to anti-CD3 and to the superantigen SEA. TB rats with small tumors had a stronger response to IL-18-producing H1D2 stimulator cells than to wild type H1D2 cells. This was not the case with TB rats carrying larger tumors. Also the IFN-gamma production and cytotoxicity against the wild-type tumor cells and the NK sensitive YAC cells were depressed in spleen cells of TB rats after 5-day restimulation with wild-type tumor cells. A part of this immunosuppression was mediated by adherent spleen cells, mostly consisting of macrophages. An important mode of action appears to involve their production of an enhanced level of nitric oxide, since the competitive nitric oxide synthase (NOS) inhibitor L-NAME could partially counteract the suppression in vitro. We conclude that NOS inhibitors in combination with immunostimulatory cytokines, such as IL-18, could be useful tools to enhance anti-tumor immune responses in TB rats and therefore to increase the efficiency of immunotherapies.     

Adenomatous polyposis coli-deficient zebrafish are susceptible to digestive tract neoplasia

Truncation of the tumour suppressor adenomatous polyposis coli (APC) constitutively activates the Wnt/beta-catenin signalling pathway. This event constitutes the primary transforming event in sporadic colorectal cancer in humans. Moreover, humans or mice carrying germline truncating mutations in APC develop large numbers of intestinal adenomas. Here, we report that zebrafish that are heterozygous for a truncating APC mutation spontaneously develop intestinal, hepatic and pancreatic neoplasias that are highly proliferative, accumulate beta-catenin and express Wnt target genes. Treatment with the chemical carcinogen 7,12-dimethylbenz[a]anthracene accelerates the induction of these lesions. These observations establish apc-mutant zebrafish as a bona fide model for the study of digestive tract cancer.     

A new DNA marker (D4S90) is located terminally on the short arm of chromosome 4, close to the Huntington disease gene

Genetic linkage studies have mapped Huntington's disease (HD) to the distal portion of the short arm of chromosome 4 (4p16.3), 4 cM distal to D4S10 (G8). To date, no definite flanking marker has been identified. A new DNA marker, D4S90 (D5), which maps to the distal region of 4p16.3, is described. The marker was used in a genetic linkage study in the CEPH reference families with seven other markers at 4p16. The study, together with knowledge of the physical map of the region, places D4S90 as the most distal marker, 6 cM from D4S10. A provisional linkage study with HD gave a maximum lod score of 2.14 at a θ of 0.00 and no evidence of linkage disequilibrium. As D4S90 appears to be located terminally, it should play an important role in the accurate mapping and cloning of the HD gene.     

Effect of smooth muscle tone on morphometry and residual strain in rat duodenum, jejunum and ileum

It is difficult to measure gastrointestinal smooth muscle (SM) tone except in sphincter regions. Since tone affects the biomechanical properties, the aim of the present study was to evaluate intestinal SM tone by studying the morphometry and biomechanical properties with and without muscle tone. Circumferential rings of 0.8-1mm in width were cut from the rat duodenum, jejunum and ileum. Sectors were obtained by cutting the rings opposite to the mesentery. The rings and the sectors were immersed in physiological Krebs solution in order to maintain the tone and into Krebs solution without Ca(++) and with EGTA to abolish the tone. The circumferences, area, the circularity and residual strain of the mucosal and serosal surfaces, opening angle, and opening angle tone/non-tone ratio were measured or computed. The tone affects the opening angle and residual strain in the intestinal sectors. The opening angle in the tissue sectors with tone was smaller (P<0.05) than those without tone in all three segments. The opening angle tone/non-tone ratio was 0.40+/-0.05, 0.43+/-0.06 and 0.36+/-0.11 for duodenum, jejunum and ileum, respectively, and did not differ among the three intestinal segments. The residual strain between sectors with and without SM tone differed in duodenal and jejunal mucosa and in the serosa of all three segments (P<0.05). The intestinal rings with tone showed axial variation for luminal area (P<0.001), for wall area (P<0.05), and for the mucosal and serosal residual strains (P<0.05). In conclusion, the intestinal mechanical properties are affected by intestinal SM tone. The tone can be evaluated by measuring the opening angle and residual strains of sectors in intestinal segments with and without SM tone.